US3923985A - Process for the preparation of 16{60 -methyl-{66 {hu 1,4,9(11){b -pregnatrien-3,20-diones and use of the same in treatment of allergies - Google Patents

Process for the preparation of 16{60 -methyl-{66 {hu 1,4,9(11){b -pregnatrien-3,20-diones and use of the same in treatment of allergies Download PDF

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Publication number
US3923985A
US3923985A US491339A US49133974A US3923985A US 3923985 A US3923985 A US 3923985A US 491339 A US491339 A US 491339A US 49133974 A US49133974 A US 49133974A US 3923985 A US3923985 A US 3923985A
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methyl
pregnatrien
formula
treatment
product
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Expired - Lifetime
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US491339A
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English (en)
Inventor
Jacques Prost Marechal
Georges Tomasik
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Sanofi Aventis France
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Roussel Uclaf SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond

Definitions

  • the invention relates to a process for the production of l6a-methyl-A"- ""-pregnatrien-3,ZO-diones having the formula wherein R is hydrogen or the acyl of a carboxylic acid having 1 to 18 carbon atoms, pharmacological preparations containing said l6a-methyl-A"' pregnatrien-3,20-diones and methods of treating allergies using the above pharmacological preparation.
  • An object of the present invention is the development of a process for the treatment of allergic reactions in warrnblooded animals which consists in administering a safe but effective amount of a l6a-methyl- A" '"-pregnatrien-3,20-dione having the formula CHZOR wherein R is a member selected from the group consisting of hydrogen and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, to a warmblooded animal undergoing an allergic reaction.
  • a further object of the present invention is the development of pharmaceutical compositions for the treatment of allergic reactions comprising a minor amount of the above lot-methyl-A"' -pregnatrien-3,20- diones and a major amount of a pharmacological excipient.
  • a yet further object of the present invention is the development of a process for the production of a 160:- methyl-A "-pregnatrien-3,20-dione having the formula wherein R is a member selected from the group consisting of hydrogen and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, which consists essentially of the steps of subjecting a compound having the formula 1 (IJH OR wherein R is the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, to the action of a methyl magnesium halide in the presence of an inert anhydrous organic solvent, and recovering said 16amethyl-A" "-pregnatrien-3,20-dione.
  • R represents an acyl radical
  • it is preferably the acyl of an alkanoic acid having from 1 to 12 carbon atoms such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, trimethylacetic acid, B-trimethyl-propionic acid or undecylic acid, or the acyl of a cycloalkanoic acid having 4 to 8 carbon atoms such as cyclopropylcarboxylic acid, cyclobutylcarboxylic acid, cyclohexylcarboxylic acid, etc, or also the acyl of an aromatic hydrocarbon carboxylic acid containing from 7 to 12 carbon atoms, such as benzoic acid or phenylacetic acid.
  • the compounds of formula I present especially a very marked anti-allergic activity while having only a very poor anti-inflammatory activity.
  • the compounds of formula I are about 1000 times less anti-inflammatory than dexamethasone and only about 50 times less antiallergic. This disassociation of properties is of great interest, because it is possible to use the compounds of formula I at dosages where only its anti-allergic properties are manifested.
  • the compounds of formula I are devoid of the classic secondary effects of the glucocorticoids and present an excellent therapeutic margin.
  • the present invention relates to a process for the treatment of allergic reactions in warmblooded animals which consists in administering a safe but effective amount of a lGa-methyl-A- -pregnatrien-3,20-dione having the formula wherein R is a member selected from the group consisting of hydrogen and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, to a warmblooded animal undergoing an allergic reaction.
  • compositions containing, as active principle, at least one compound of formula I are pharmaceutical compositions for the treatment of allergic reactions in warm-blooded animals comprising a minor amount of a l6a-methyl-A- -pregnatrien- 3,20-dione having the formula CHZOR wherein R is a member selected from the group consisting of hydrogen and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, and a major amount of a pharmaceutical excipient.
  • compositions can be solid or liquid and are presented in the pharmaceutical forms currently used in human therapy for oral, parental or rectal administration. These are, for example, tablets or coated tablets, gelules, syrups or suspensions, injectable solutes or suspensions or suppositories. These pharmaceutical forms are prepared accordingly to the usual methods.
  • the compounds of formula I can be compounded with the usual excipients employed in pharmaceutical compositions such as talc, arabic gum, lactose, starch,
  • the useful dosology of the compounds of formula I is controlled for example between 10 mg and 200 mg per day orally, in the adult, or from 0.2 to 4 mg/kg per day in the warm-blooded animal.
  • the compounds utilized as starting materials of formula II can be prepared according to the method given in US. Pat. No. 2,864,834.
  • the preferred value for both R and R is acetyl.
  • the methyl magnesium halide utilized is methyl magnesium bromide or methyl magnesium chloride.
  • reaction between a compound of formula II and the methyl magnesium halide is effected in the presence of an inert anhydrous organic solvent, preferably an ether, such as diethyl ether, dioxane or tetrahydrofuran, and in the presence of a catalyst such as, for example a copper salt, such as cuprous chloride.
  • an inert anhydrous organic solvent preferably an ether, such as diethyl ether, dioxane or tetrahydrofuran
  • a catalyst such as, for example a copper salt, such as cuprous chloride.
  • reaction is conducted at a temperature between 50C and +C.
  • esterification reaction if employed, is effected by employing an acid or a functional derivative thereof, for example an acid chloride or acid anhydride, in the presence of a base, such as pyridine.
  • the invention also relates to a variant of the preceeding process characterized in that a compound of the formula II'.--
  • EXAMPLE 3 Example of a Pharmaceutical Form Tablets were produced weighing 150 mg and containing 20 mg of the product of Example 2 (hereinafter called Product A), from the following recipe:
  • Product A was studied comparatively to dexamethasone. The two compounds were utilized in suspension in an aqueous vehicle containing 0.25 percent of carboxymethylcellulose and 0.20 percent of Polysorbate 80 (a polyoxyethylated sorbitol mono-oleate).
  • ANTI-INFLAMMATORY ACTIVITY This was determined according to the classic granuloma technique. The technique used was modified from the Meier et al method (Experientia, 1950, 6, 469). Some conventional female Wistar rats, weighing to l 10 gm, received an implantation of two pellets of cotton weighing 10 mg each, under the skin of the thorax. The oral treatment, which started immediately after this implantation, lasted two days, at a rate of two administrations per day. 16 hours after the last ingestion, i.e. on the third day, the animals were sacrificed.
  • the pellets surrounded by the tissue of granuloma formed were weighed once in the fresh state, then after drying for 18 hours at 60C. The weight of the granuloma was obtained after deduction of the initial weight of the cotton.
  • the weight of the thymus, separated at the same time as the granulomas, enabled a determination of the thymolytic activity of the tested compounds.
  • Product A begins to manifest a weak anti-granulomatosic activity but no thymolytic effect at a dose of 20 mg/kg.
  • the inhibition of granuloma and the involution of the thymus attained about a 35 percent level.
  • the 50 percent active dose (AD of dexamethasone is about 0.05 mg/kg on both the granuloma and the thymus.
  • the anti-inflammatory effect of Product A is thus more than 1000 times less than that of dexamethasone. Moreover, to the contrary of the effect of dexamethasone, Product A has very little effect on the body growth of animals even at the great dosages utilized here.
  • biogenic amines especially serotonine, by the mastocytes.
  • the tests were conducted on groups of eight male rats of the Sprague Dawley SPF strain, weighing from 110 to 130 gm. Dextran was administered at a dose of 150 mg/kg in a volume of 1 ml per 100 gm and the degree of edema was evaluated one hour afterwards. That of the nose and fore paws was evaluated according to an arbitrary scale going from 0 to 3 and that of the hind paws by measurement of their volume with a mercury plethysmometer, of which 12 units correspond about to Ice.
  • the other product of Formula I have comparable pharmacological properties.
  • compositions for the treatment of allergic reactions of seasonal or aperiodic rhinitis, spasmodic coughing, asthma and skin disturbances in warm-blooded animals comprising a minor amount of l6a-methyl-A -pregnatrien-3,ZO-dione having the formula cn on wherein R is a member selected from the group consisting of hydrogen and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, to a warmblooded animal undergoing said allergic reaction.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US491339A 1973-07-27 1974-07-24 Process for the preparation of 16{60 -methyl-{66 {hu 1,4,9(11){b -pregnatrien-3,20-diones and use of the same in treatment of allergies Expired - Lifetime US3923985A (en)

Applications Claiming Priority (1)

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FR7327578A FR2244530B1 (enrdf_load_stackoverflow) 1973-07-27 1973-07-27

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US3923985A true US3923985A (en) 1975-12-02

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US (1) US3923985A (enrdf_load_stackoverflow)
JP (1) JPS5830319B2 (enrdf_load_stackoverflow)
BE (1) BE818155A (enrdf_load_stackoverflow)
CA (1) CA1029659A (enrdf_load_stackoverflow)
CH (1) CH594698A5 (enrdf_load_stackoverflow)
DE (1) DE2436234A1 (enrdf_load_stackoverflow)
DK (1) DK401974A (enrdf_load_stackoverflow)
FR (1) FR2244530B1 (enrdf_load_stackoverflow)
GB (1) GB1480763A (enrdf_load_stackoverflow)
IE (1) IE40163B1 (enrdf_load_stackoverflow)
IL (1) IL45344A (enrdf_load_stackoverflow)
NL (1) NL7410093A (enrdf_load_stackoverflow)
SE (1) SE7409158L (enrdf_load_stackoverflow)
ZA (1) ZA744750B (enrdf_load_stackoverflow)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603842A (zh) * 2012-02-20 2012-07-25 湖南诺凯生物医药有限公司 醋酸氢化可的松或其类似物的制备方法
CN103739647A (zh) * 2008-05-28 2014-04-23 雷沃根生物医药有限公司 用于治疗疾病的NF-κB的非激素甾体调节剂
US9198921B2 (en) 2010-04-05 2015-12-01 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US10799514B2 (en) 2015-06-29 2020-10-13 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kappa beta for treatment of disease
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2383968A1 (fr) * 1977-03-18 1978-10-13 Roussel Uclaf Procede de preparation d'un steroide16a-methyle

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB929429A (en) * 1958-09-08 1963-06-26 Merck & Co Inc Preparation of steroid compounds
GB935611A (en) * 1958-12-20 1963-08-28 Syntex Sa New cyclopentanophenanthrene derivatives and process for the production thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1461655A (fr) * 1965-10-28 1966-02-25 Roussel Uclaf Nouveau procédé de préparation d'un dérivé corticostéroïde et produits obtenus dans ce procédé

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB929429A (en) * 1958-09-08 1963-06-26 Merck & Co Inc Preparation of steroid compounds
GB935611A (en) * 1958-12-20 1963-08-28 Syntex Sa New cyclopentanophenanthrene derivatives and process for the production thereof

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10857161B2 (en) 2008-05-28 2020-12-08 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
US10206933B2 (en) 2008-05-28 2019-02-19 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
US11833159B2 (en) 2008-05-28 2023-12-05 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
KR20160015408A (ko) * 2008-05-28 2016-02-12 레베라겐 바이오파마 인코포레이티드 질환의 치료를 위한 ＮＦ-κＢ 의 비호르몬성 스테로이드 조절제
US9434758B2 (en) 2008-05-28 2016-09-06 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
CN103739647B (zh) * 2008-05-28 2017-06-09 雷沃根生物医药有限公司 用于治疗疾病的NF‑κB的非激素甾体调节剂
CN103739647A (zh) * 2008-05-28 2014-04-23 雷沃根生物医药有限公司 用于治疗疾病的NF-κB的非激素甾体调节剂
US10000525B2 (en) 2010-04-05 2018-06-19 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US9198921B2 (en) 2010-04-05 2015-12-01 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
CN102603842A (zh) * 2012-02-20 2012-07-25 湖南诺凯生物医药有限公司 醋酸氢化可的松或其类似物的制备方法
US10799514B2 (en) 2015-06-29 2020-10-13 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kappa beta for treatment of disease
US11690853B2 (en) 2015-06-29 2023-07-04 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κβ for treatment of disease
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions
US11471471B2 (en) 2019-03-07 2022-10-18 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions
US12201639B2 (en) 2019-03-07 2025-01-21 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

Also Published As

Publication number Publication date
BE818155A (fr) 1975-01-27
SE7409158L (sv) 1975-01-28
FR2244530A1 (enrdf_load_stackoverflow) 1975-04-18
IE40163L (en) 1975-01-27
IL45344A (en) 1978-08-31
AU7165974A (en) 1976-01-29
CH594698A5 (enrdf_load_stackoverflow) 1978-01-31
DE2436234A1 (de) 1975-02-13
JPS5041847A (enrdf_load_stackoverflow) 1975-04-16
IE40163B1 (en) 1979-03-28
GB1480763A (en) 1977-07-27
FR2244530B1 (enrdf_load_stackoverflow) 1977-07-01
IL45344A0 (en) 1974-10-22
NL7410093A (nl) 1975-01-29
JPS5830319B2 (ja) 1983-06-28
ZA744750B (en) 1975-08-27
DK401974A (enrdf_load_stackoverflow) 1975-04-01
CA1029659A (en) 1978-04-18

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